neuron lecture 2012 de camilli final amedcell.med.yale.edu/lectures/files/neurons.pdf · neuron...

Neurons(and glial cells)

Pietro De Camilli

October 11, 2012

Human Brain

Peter Takizawa

Grey matter

Peter Takizawa

White matter

Peter Takizawa

Golgi Stain

Camillo Golgi

Peter Takizawa

He mistakenly left brain sample in silver stain overnight. Next day he looked at slices of brain under a microscope and saw these cells which are neurons.

Peter Takizawa

Cajal

Peter Takizawa

Cajal used Golgi stain to describe the structure of neurons and define axons and dendrites.

Peter Takizawa

Genetically encoded dyes

green fluorescent proteinAequorea victoria

Jeff Lichtman

Martin Chalfie

Roger Tsien

Peter Takizawa

Genetic dyes (GFP and variants) can be used to label individual neurons.

Peter Takizawa

Jeff Lichtman

Brainbows

Genetically encoded dyes

Peter Takizawa

An example of expressing differently colored protein dyes in neurons. Allows one to visualize distinct neurons and examine thier connections.

Peter Takizawa

Neurons have a variety of shapes

Peter Takizawa

Cajal found that neurons have a variety of shapes. Researchers are trying to determine how the expressions of different genes generate these unique cellular shapes.

Peter Takizawa

axon

dendrites

Neuron as polarized cells

axon

Stages of axonal development (in vitro)

Dotti and Banker

(typically only one)

Peter Takizawa

Neurons: Cell body with axon and dendrites. Dendrites are extensions of cell body have most of the components that are found in the cell body. Dendrites receive input from other cells. Axons are more specialized. Usually only one axon per neuron, but they can branch. Neurons in culture will develop axons and dendrites in the absence of other cells but require growth factors.

Peter Takizawa

Red: axonal markerGreen: dendritic marker

Nerve cell grown in vitro

DENDRITES(INPUT)

AXON(OUTPUT)

Axon and dendrites have different properties

perikaryonsomacell body

Peter Takizawa

Axons and dendrites have different molecular compositions as shown by this image of a neuron in culture. Note that the axon synapses onto one of the dendrites from the same cells.

http://www.clp.northwestern.edu/news/rewrite-textbooks-findings-challenge-conventional-wisdom-how-neurons-operate

Inhibitory interneuron (dendrites blue, axon red) shown adjacent to a schematic

of a hippocampal pyramidal neuron

Both dendrites and axons can be extremely branchedaxons are typically longer (can be much longer)

axon and dendrites of a single neuron

Demian Barbas, Luc DesGroseillers, Vincent F. Castellucci, et al. Learn. Mem. 10: 373, 2003

Neurons are organized in neuronal circuits

Schematic diagram of the neuronal circuit mediating tail and siphon withdrawal reflex in Aplysia (an invertebrate organism)

Peter Takizawa

Dendrite

Peter Takizawa

Axon

Peter Takizawa

Cell Body

Peter Takizawa

Synapse

Peter Takizawa

Key compartments of the neuron:

cell body (soma, perikaryon)dendritesaxons

Motor NeuronsVentral Horn

Dendrite

Nissl substance = RERCell body or perikaryon

Axon hillock

blood capillary

Neuronal perikarya

Most organelles of the cell body extend into the main dendritic branches

Peter Takizawa

Cell bodies of neurons can be very large. Must support long, branched axons and dendrites. Neurons last for life of organism. Most organelles in cell bodies extend into dendrites (e.g. ER). Axon is more selective about which organelles can enter from the cell body. All protein synthesis machinery is in cell body or dendrites. Axons can make lipid but lack protein synthesis machinery.

Peter Takizawa

Motor NeuronsVentral Horn

Dendrite

Nissl substance = RERCell body or perikaryon

Axon hillock

blood capillary

Neuronal perikarya

Axon hillock

Entry of organlles in axons is selective. There are no rough

endoplasmic reticulum or ribosomes (and thus no protein synthesis) and Golgi complex in

mature axons

axons

Dendritic trees

Purkinje cells (cerebellum)

Dendritic spines

Peter Takizawa

Dendrites integrate inputs from many different axons (can receive 1000s of inputs). Each synapse contributes a small amount of depolarization of the neuron. If the sum of the signals is sufficient, an action potential will be triggered in the axon.

Peter Takizawa

Neuron Cytoplasm

Golgi Complex

RER

Golgi complex

Neuron Cytoplasm

Golgi Complex

RER

immunofluorescence

Silver impregnation(From Camillo Golgi)

Golgi complex

Peter Takizawa

Golgi complex extends into dendrites but not axons.

Peter Takizawa

Axon sizeThe length of the axons

poses special needs:

-Structural support-Assisted organelle transport-Local synthesis and degradation of metabolites-Signal propagation

Peter Takizawa

Axons can be extremely long compared to the cell body. Neurons need deliver machinery down the axon. Need structural support both internally (cytoskeleton) and externally. Neurons deliver signals via their axons to specific cells, similar to phone cables that make specific connections. Because axons make specific contacts, few different types of neurotransmitters are used.

Unmyelinated Axons

Axons are surrounded by glial cells

Peter Takizawa

Glia cells provide external support to axons. Microtubules and neurofilaments, a type of intermediate filaments provide internal support.

Peter Takizawa

Microtubule

Peter Takizawa

AxonMyelinated

axon

Schwann cells (PNS)Oligodendrocytes (CNS)

Axons are surrounded by glial cells

Peter Takizawa

Myelin sheath wraps axons

Peter Takizawa

Myelin

Development of myelin Node of Ranvier

Peter Takizawa

S

Peter Takizawa

Gaps in myelin sheath are created where adjacent glia cells meet on the axon. These gaps are called nodes of Ranvier.

Peter Takizawa

Myelin

Development of myelin Node of Ranvier

Node of Ranvier, EM

Node of Ranvier

Nodes of Ranvier

βIV-spectrinK+ channelK+ channel Na+ channel

mutation:quivering mouse

Peter Takizawa

Myelin prevents depolarization of membrane but nodes contain sodium channels. Action potential jumps from node to node generating fast, saltatory conduction.

Peter Takizawa

Node of Ranvier

Peter Takizawa

Myelinated Axonlongitudinal-section

Quick-freeze-deep-etch viewFrom Hirokawa

A prominent cytoskeletal scaffold

Peter Takizawa

Cytoskeleton provides structural support and creates tracks for transport of cellular material.

Peter Takizawa

Axonal transport• Anterograde, slow 2-4 mm/day

– cytosolic proteins, cytoskeletal elements…• Anterograde, fast (kinesins) 100-400 mm/day

– organelles, particles

• Retrograde, fast (cytoplasmic dynein)– organelles, particles (retrograde signaling, targeting to

lyososomes)

Peter Takizawa

Toward axon terminus

Peter Takizawa

Toward cell body

Peter Takizawa

Organelle transport(microtubular motors in axonal cytoplasm)

From Paul ForscherFrom Nabutaka Hirokawa

Microtubular motors:kinesin(s) and cytoplasmic dynein

A multiplicity of kinesins(different cargo vesicles)

Peter Takizawa

Different types of kinesin are responsible for transporting different kinds of cellular organelles.

Weiss axoplasmic flow

Proximal to axonal block Distal to axonal block

From Tsukita and Ishikawa

Axonal block

Peter Takizawa

Newly made material accumulates on proximal side of block

Peter Takizawa

Old material accumulates on distal side of block.

Peter Takizawa

From Broadwell and Cataldo, 1984

A continuous smooth ER from the cell body to axon terminal

arrows = endoplasmic reticulum

Several forms of hereditary spastic paraplegias are due to mutations in proteins that control the shape and the dynamics of the ER

Peter Takizawa

Axons contain smooth ER to synthesize lipids.

closedinactivated

openedclosed

unmyelinated nerveConduction 0.6-2 m/sec + + + +

+ + + + ++ + + + +

- - - - - + +

Signal propagation in axons

Na+

Na+K+

K+

140 mM

17 mM

4.6 mM

90 mM

-70 mV

Unmyelinated nerve

gradient of Na+ and K+ across the plasma membrane is mantained by Na+/K+ ATPase

Na+ channel

inactivated opened closed

Conduction 5-120 m/sec - -

- -

+ +

Signal propagation in axonsMyelinated nerve

Saltatory conduction

nodes of Ranvier

DIC

Microtubules

ActinfilamentsLab of Paul Forscher Elke Stein

Growth cones

attraction/repulsion

Peter Takizawa

Guide growth and development of axons. Are attracted to and repulsed by specific chemicals that guide the direction of their growth.

Peter Takizawa

Growth Cone

Lab of Paul Forscher, Yale

Axonal Degeneration and Regeneration

Axon regeneration occurs in the peripheral

nervous system but does not occur in the white matter of the

central nervous system

white matter gray matter

Peter Takizawa

Myelin made by Schwann cells inhibit growth of axons in CNS. Prevents overgrowth of axons to maintain fidelity of connections.

Model organisms

302 neurons (instead of billions as in the human brain)

Caenorhabditis elegans

daf-18 mutantwild type

Colon Ramos labAIY neurons

tools to study principles in neurons and circuits development

Axonal Regeneration

RegenerationAxotomy

Lab of Marc Hammarlund, Yale CNNR

Glial cells

ASTROCYTES

Structural supportPhysical isolation of neuronsBuffer of extracellular ions (f.e.sink for K+)Uptake /clearance of of neurotransmittersMetabolic functions to support neuronsSecretion of growth factorsResponse to injuryBlood-brain barrier

Astrocyte

Radial gliatracks for neuronal migration during brain development

developing cerebral cortex: the youngest cells are the ones closests to the pial surface

from F. Polleaux

Myelin generating cells:Oligodendrocytes (CNS) & Schwann cells (PNS)

Schwann cells = peripheral nervous system

Oligodendrocytes = central nervous system

Multiple Sclerosis (MS)

1. Inflammation2. Demyelination3. Impairment of nerve conduction4. Neurological deficits

Macrophage engulfing myelin in experimental autoimmune

encephalytis (EAE)��mouse model for MS

plaques

RemyelinationI. Recruitment phase

(Proliferation, Migration)

Acute lesion Recruitment of OPCs

Oligodendrocyte progenitor cells (OPCs)Franklin NatRevNeurosci 2002

Microgliathe macrophages of the brain

Microglia

Wenbiao Gan (NYU)

Neurodegeneration

Alzheimer plaques

iPS cells

Dimos/Eggan Lab at HSCI.

Motor neurons from patient with ALS

John B. Gurdon, Shinya Yamanaka2012 Physiology and Medicine Nobel Prize

Gensat projecthttp://www.gensat.org/index.html

NIH funded, publicly available gene expression atlas of the developing and adult nervous system

different shapes and differential gene expression

neuron lecture 2012 de camilli final amedcell.med.yale.edu/lectures/files/neurons.pdf · neuron...

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